1. Field of the Invention
The present invention relates to an apoptosis inhibitor. More particularly, relates to a novel apoptosis inhibitor containing isocarbacyclin derivative, which has been known as a ligand specific to prostacyclin receptors of the central nervous system. The inhibitor has an excellent inhibiting action to apoptosis of nerve cells, etc.
2. Description of the Related Art
Apoptosis is a kind of genetically programmed cell death and, morphologically, it takes place according to the following processes: aggregation of nucleus; cell contraction; vacuole formation; smoothening of cell surface; expansion of intercellular intervals; liberation of cells from the surroundings; fragmentation of cells (apoptosis corpuscles); and phagocytosis by macrophage, etc. It has also been known that, biochemically, nucleosome unit of DNA is fragmented by endonuclease activity into DNA of base length of 180-200 (Immunology Today, 7:115-119, 1986; Science, 245:301-305, 1989).
At present, it has been clarified that, in addition to physiological functions such as development/differentiation and turnover of normal tissues and cells, this apoptosis participates in certain diseases such as inflammation and reduction of lymphocytes caused by ischemic nerve cell death after cerebral infarction, etc., involution of carcinoma, action of radioactive ray and anticancer agent and infection of virus such as AIDS. Thus, development of drugs for controlling apoptosis (i.e., apoptosis inhibitors and apoptosis inducers) has been expected to give birth to drugs based on new action mechanisms in the broad areas including central nervous system as well as cancer, aging, etc.
With regard to substances and factors for inducing apoptosis, toxicity of neurotransmitters such as glucocorticoid and glutamic acid, irradiation of radioactive ray, NK cells, killer cells, tumor necrosis factor (TNF), cytokines such as lymphotoxin (LT), etc. have been reported. It has also been reported that cycloheximide which is a protein synthesis inhibitor or actinomycin D which is an RNA synthesis inhibitor induces apoptosis to human leukemia cells HL-60. Further, anti-Fas monoclonal antibody to Fas antigen which is a cell membrane molecule participating in apoptosis of immune cells has been prepared recently and various investigations have been conducted for application of anti-Fas antibody to pharmaceuticals.
On the other hand, substances which inhibit interleukin 1 converting enzyme, basic fibroblast growth factor (bFGF), etc. have been reported as factors for inhibiting apoptosis. It has also been known that bcl-2 related gene products inhibit apoptosis and have a macrobiotic function for cells. However, all of those apoptosis inhibiting factors are derived from living organisms and, up to now, no apoptosis inhibitor obtained by industrial means such as chemical synthesis has yet been known.
On the other hand, during the course of investigation of physiological action of brain function in detail, the inventors of the present application have found various isocarbacyclins acting as specific ligands to prostacyslin ruchptor of the central nerve system and have filed patent applications already [Japanese Patent Application Nos. 051,589/,96 (JP-A 245,498/96), 243,122/96 (JP-A 87608/98), 260,957/96 (JP-A 101610/98) and 160,320/97]. As a result of further investigation on the physiological activity of those subtances, several of them have been found to show a significant apoptosis inhibiting effect.
Accordingly, an object of the present invention is to offer a novel apoptosis inhibitor which can be manufactured by means of chemical synthesis in large quantities and also at low cost by a further development of the above-mentioned findings by the present inventors.